Perfluoroalkanesulfonamide Organocatalysts for Asymmetric Conjugate Additions of Branched Aldehydes to Vinyl Sulfones

Asymmetric conjugate additions of branched aldehydes to vinyl sulfones promoted by sulfonamide organocatalyst 6 or 7 have been developed, allowing facile synthesis of the corresponding adducts with all-carbon quaternary stereocenters in excellent yields with up to 95% ee.

On the other hand, fluorous compounds with a perfluoroalkyl group can be easily separated from nonfluorous compounds by fluorous organic solvent extraction or fluorous solid phase extraction (FSPE) using fluorous silica gel [39]. Several research groups have reported asymmetric reactions in which fluorous organocatalysts are recyclable [40]. We have also reported a direct aldol reaction in water using fluorous sulfonamide organocatalyst 3 and related catalysts [41][42][43], Michael addition reactions using a fluorous thiourea organocatalyst [44], and an oxidation reaction using fluorous IBX [45]. In addition, we have reported a method for the synthesis of both enantiomeric aldol products in water using sulfonamide organocatalysts 1 [46] and 2 [47,48], prepared from L-phenylalanine. Very recently, we reported in a preliminary communication that perfluoroalkanesulfonamides 5 and 6 catalyze the conjugate additions of branched aldehydes to vinyl sulfone 11 to give the corresponding adducts with excellent stereoselectivities [49]; however, development of a protocol for recovery and reuse of 5 and 6 is yet to be reported. Herein, we describe the full details of the conjugate additions of branched aldehydes to vinyl sulfone using 6 and novel fluorous sulfonamide 7 ( Figure 1).

Results and Discussion
We initially examined the sulfonamide organocatalysts 1-7 for the conjugate addition of 12a to 11 as a test reactant (Table 1). Sulfonamide organocatalysts 1-4 derived from L-phenylalanine were superior to catalyst 5 derived from L-valine for the direct aldol reactions in water [37,46,48]; however, 5 bearing the valine skeleton resulted more suitable for the conjugate addition with vinyl sulfone 11 (entries 1-5). Furthermore, to develop a more powerful organocatalyst, we synthesized 6, which enhanced the acidity of the sulfonamide group by the introduction of the perfluorobutyl group. Treatment of compound 8 [50] with perfluorobutanesulfonyl fluoride in presence of triethylamine in dichloromethane provided the intermediate 9 in 79% yield. The Boc protective group was removed by treatment of hydrogen chloride in ethyl acetate to give the desired perfluorobutanesulfonamide 6 in 90% yield (Scheme 1). Organocatalyst 6 was more effective for conjugate additions with vinyl sulfone 11, resulting in the highest enantioselectivity (91% ee) and excellent yield (entry 6). Furthermore, to develop an organocatalyst that can be recovered and reused, 7 was synthesized by a similar procedure (Scheme 2). The stereoselectivity was slightly reduced in the reaction using 7 (entry 7).  We investigated the optimal reaction conditions for the enantioselective conjugate additions using 6, various solvents, and additives ( Table 2). Conjugate additions were performed with vinyl sulfone 11 and 2-methylphenylethanal (12a) as test reactants in the presence of a catalytic amount of 6 and trifluoroacetic acid (TFA) at room temperature. A slight reduction in enantioselectivity and much longer reaction time were observed without TFA (entries 1 and 2). Aprotic solvents such as dichloromethane, diethyl ether, ethyl acetate, acetonitrile, chloroform, 1,2-dichloroethane, and p, m, and o-xylene were accepted well in this conjugate addition with good enantioselectivity (entries 3 and 5-12). A protic polar solvent such as methanol is a poor solvent for this reaction and provided low yield and enantioselectivity (entry 4). Among the solvents probed, the best results (95% yield and 93% ee) were NHSO 2 C 4 F 9 H 2 N achieved when the reaction was performed in m-xylene (entry 11). We also examined the effects associated with the presence of other protic acids, including benzoic acid, p-nitrobenzoic acid, and trifluoromethanesulfonic acid; however, TFA was found to be the most suitable additive (entries 13-15). Additions of 0.2 or 0.05 equiv of TFA resulted in a slight reduction in stereoselectivity (entries 16 and 17). The highest enantioselectivity (95% ee) was obtained when the reaction was performed at 0 °C or −10 °C, although longer reaction time (21 h or 72 h) was required (entries 18 and 19). Enantioselectivity was slightly reduced when the catalyst loading was lowered to 0.05 equiv (entry 20). Considering the reaction time, the optimal conditions were determined to be 0.1 equiv of 6 and 0.1 equiv of TFA in m-xylene at room temperature (entry 11). In order to identify the scope and limitations of aldehyde substrates, we investigated substituent effects of the branched aromatic aldehydes on the conjugate additions (Table 3). A range of electron-withdrawing substituents such as bromo and fluoro moieties, and electron-donating substituents such as methyl and methoxy groups on the aromatic ring of branched aldehydes 12b-g provided the corresponding adducts in excellent yields with good enantioselectivities (83%-92% ee) (entries 2-7). The additions of branched aldehydes possessing a naphthalene motif, 12h and 12i, to vinyl sulfone 11 proceeded smoothly in the presence of a catalytic amount of 6 to afford the corresponding adducts 13h and 13i in excellent yields with 92% ee, respectively (entries 8 and 9). Interestingly, 2-methoxy-2-phenylacetaldehyde (12j) was also applicable and gave the corresponding adduct 13j in high yield, albeit with reduced enantioselectivity (entry 10). In addition, 6 promoted the reaction of N-Boc α-aminophenylacetaldehyde (12k) with 11 to yield the corresponding adduct 13k in 68% yield with 60% ee (entry 11). Based on the optimal conditions for conjugate additions using 6, the reaction conditions were optimized for the enantioselective conjugate additions using 7 (Table 4). 1,2-Dichloroethane was the most suitable solvent among those examined in the presence of 0.1 equiv of TFA at room temperature. The reaction in 1,2-dichloroethane provided high yield and enantioselectivity (entry 8). It should be noted that 7 can promote the conjugate additions in brine because the perfluoroalkyl chain of 7 functions as the hydrophobic reaction field in water as described in our previous report [42,43]. The generality and substrate scope were probed for the optimal conditions ( Table 5). The tendency of reactivities using 7 was quite similar to that using 6; however, aldehydes 12e, 12i, and 12j were poor substrates and gave low to moderate yields (entries 5, 9, and 10). Interestingly, the stereoselectivity with 12g was improved up to 94% ee (entry 7). In addition, the yield in the reaction with 12k was improved up to 100% yield (entry 11).
The recyclability of 7 was evaluated. After use of 7 in the conjugate addition of 12a to 11 under the optimal conditions, it was readily recovered by the FSPE technique using fluorous silica gel. Furthermore, the recovered catalyst 7 can be reused without further purification, and its catalytic activity was retained for the first reuse. Unfortunately, the catalytic activity of the recovered catalyst 7 decreased significantly for the second reuse.
We infer that the conjugate additions of aldehydes 12 to vinyl sulfone 11 using 6 or 7 proceed via a plausible transition state (Scheme 3) based on the stereochemistry of addition products 13a-i. The primary amino group of 6 or 7 condenses with aldehydes 12 to generate the corresponding imine intermediate. The imine intermediate is subsequently isomerized to the E-enamine intermediate because of the resonance stabilizing effect of the aromatic ring. Then, the acidic proton of the sulfonamide group, which coordinates intramolecularly to nitrogen in the enamine transition state, successfully interacts with the oxygen of vinyl sulfone to control the approach direction of vinyl sulfone to the Re face of the enamine intermediate. This ultimately affords the corresponding addition products with high stereoselectivities. We believe that the acidity of 6 and 7 is enhanced by the powerful electron-withdrawing effect of the perfluoroalkyl chains, enabling strong coordination to vinyl sulfone and stabilizing the rigid transition states during conjugate additions. Moreover, the addition of TFA to the conjugate additions might accelerate the formation of the imine and enamine intermediates as well as reinforce the rigid transition state of the conjugate additions.

Conclusions
Novel organocatalysts 6 and 7 can easily be prepared from L-valine, an inexpensive and commercially available natural amino acid. Organocatalysts 6 and 7, which are simple β-aminosulfonamides with only one stereogenic center, efficiently catalyze the conjugate additions of various branched aldehydes to vinyl sulfone 11 with a short reaction time at room temperature to give the corresponding addition products possessing all-carbon quaternary stereocenters with high enantioselectivities. The excellent performance is probably due to the carbon skeleton of L-valine and the electron-withdrawing effect of the perfluoroalkyl groups on 6 and 7. Moreover, fluorous organocatalyst 7 bearing a perfluorooctyl group was readily recovered by simple solid phase extraction using fluorous silica gel and was immediately reusable without further purification for the first cycle. Further application of these organocatalysts in the synthesis of bioactive compounds is currently being investigated in our laboratory.